The human epidermal growth factor receptor 2 (HER2) is overexpressed in 20% of breast cancers (BCs) and confers an aggressive tumour phenotype with a poor prognosis. Trastuzumab (Herceptin®) is a humanized IgG1 monoclonal antibody (mAb) approved for treatment of HER2-positive breast cancer (BC), however many eligible patients do not respond. The hypothesis was that molecular imaging strategies that probe: i) the expression of HER2; ii) one of the mechanisms of action of trastuzumab or iii) evaluate the viability of tumour cells by their glucose utilization would be useful in predicting and monitoring the response of BC to treatment with trastuzumab. The relationship between tumour HER2 density, uptake of 111In-DTPA-trastuzumab and response to trastuzumab was evaluated by gamma camera imaging, biodistribution studies and monitoring tumour growth in mice implanted with BC xenografts. There was a non-linear relationship between HER2 expression and uptake of this radiopharmaceutical when tumour uptake was corrected for non-specific IgG accumulation and/or circulating blood radioactivity (r2=0.87-0.99). Tumour response corresponded better with the uncorrected tumour uptake of 111In-DTPA-trastuzumab. HER2 downregulation, a putative mechanism of action of trastuzumab, was noted as decreased tumour uptake on microSPECT/CT of mice bearing MDA-MB-361 xenografts administered 111In-DTPA-pertuzumab. Tumour uptake of 111In-DTPA-pertuzumab was reduced by 53% in mice treated for 3 days with trastuzumab (P<0.05) associated with an early molecular response to the drug. Furthermore, tumour uptake of 111In-DTPA-pertuzumab was reduced by 78% (P<0.001) in mice treated for 3 weeks, which corresponded with a reduction in HER2-positive tumour cells, indicating a therapeutic response. The relationship between changes in tumour uptake of 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) and response to trastuzumab was examined in mice bearing MDA-MB-361 and MDA-MB-231 BC xenografts, with high or very low HER2 expression, treated with trastuzumab. MicroPET imaging and biodistribution studies detected a 43-60% (P<0.03) reduction in tumour uptake of 18F-FDG in mice with MDA-MB-361 xenografts, treated with trastuzumab compared to PBS-treated controls. In contrast, there was no change in 18F-FDG uptake in MDA-MB-231 xenografts, that did not respond to trastuzumab. I conclude that molecular imaging is a promising tool for monitoring response of BC to treatment with trastuzumab.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/26471 |
| Date | 08 March 2011 |
| Creators | McLarty, Kristin |
| Contributors | Reilly, Raymond Matthew |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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